Composition and method for treating hemorrhoids and/or anorectal disorders

ABSTRACT

The invention provides an oil-in-water emulsion useful in the treatment of anorectal disorders comprising a local anesthetic, vasoconstrictor, glycerin and water, and method of preparation of the emulsion and a method for treating hemorrhoids using the composition of the invention.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to an oil-in-water emulsioncomposition useful in the treatment of anorectal disorders such ashemorrhoids and use of the composition in the treatment of anorectaldisorders such as hemorrhoids.

2. Description of Related Art

Hemorrhoids, a common ailment suffered by as many as nine out of tenAmericans at some point in their lives, are swollen varicose veins inthe mucous membrane inside or just outside the rectum. Hemorrhoids canbe caused by constipation and the straining associated therewith as theexcessive pressure involved can cause a fold of the membranous rectallining to slip down, resulting in a pinching of the veins and subsequentirritation. Other causes may include diseases of the digestive tractresulting in an infection and diseases which obstruct blood flow,putting increased pressure on the hemorrhoidal veins. For example,pregnant women are prone to suffer hemorrhoids because of the pressureon the veins in the abdomen.

Hemorrhoidal symptoms can range from no noticeable symptoms to itchingand mild discomfort to pain and/or bleeding. Once formed, thehemorrhoidal condition typically worsens over time, hence prompttreatment is desirable even in mild cases with few or no noticeablesymptoms.

Treatment methods for hemorrhoids include soothing by immersion in awarm bath, application of ointments, gels and suppositories and surgeryto curtail bleeding and to remove varicose veins. A single method oftreatment or combination of treatment methods may be employed.

A number of patents and patent applications disclose and claimhemorrhoidal treatments. For example, U.S. patent applicationpublication number 20040037888 discloses a gel preparation comprising acellulose gelling agent, propylene glycol, and active ingredients. Thewater based system facilitates solublization of active ingredients butlacks the desirable tactile feeling of a cream and most likely theendurance at the site of treatment of a cream.

Related U.S. Pat. Nos. 5,234,957, 5,332,576 and 5,446,070 teach acomposition comprising a polysaccharide bioadhesive carrier that ispreferably water free. Active ingredients are dissolved in a solventother than water. While this may facilitate preparation of thecomposition, the absence of water may impact the delivery of the activeingredient to body tissues. Evidence for this is found in U.S. Pat. No.5,234,957 which teaches the use of concentrations of anesthetic activessubstantially higher than approved FDA dosage amounts.

U.S. Pat. No. 6,582,724 discloses a composition which includes ahydroxide releasing agent such that the pH of the composition is pH 8.0to pH 13. Such an alkaline pH would impact the stability of many activeagents and preservation of the integrity of the composition over timewould require special efforts.

U.S. patent application publication number 20020192273 discloses anadhesive patch for application of a therapeutic formulation for thetreatment of hemorrhoids. Not only is a patch substrate required butalso a pressure sensitive adhesive. Self application of such a patch toaffected hemorrhoidal tissue may be fraught with some difficulty.Accomplishing adhesion at the desired location and/or discomfort inremoving a patch adhered to hemorrhoidal tissue are exemplary of thesedifficulties.

U.S. patent application publication number 20030054017 claims a generalmethod for application of a topical anesthetic to the skin. The methodincludes incorporating an anesthetic in a lipophilic base into avolatile solvent such as alcohol which will evaporate upon applicationto the skin. The disclosed composition is best suited for anestheticswhich are preferentially soluble in non-polar/non-aqueous medium.

Many commercial preparations are available on the market for treatmentof hemorrhoids. Many of these products are cream based preparations.Cream based compositions have the desirable properties of good tactilesensation and persistence on the area of treatment for a period of time.However, known cream based preparations typically suffer the significantdeficiency of not dissolving many topical anesthetic agents and/orvasoconstrictors which are desirable active agents. While such agentsmay be physically dispersed in a cream, homogenous distribution as wellas delivery to affected tissues may be problematic.

Hence, there remains a need for a cream type hemorrhoidal treatment withimproved compatibility with dispersion and delivery of water solubleactive agents.

SUMMARY OF THE INVENTION

The invention provides a pharmaceutical composition for treatinghemorrhoids and/or anorectal disorders comprising an effective amount ofa topical anesthetic, an effective amount of a vasoconstrictor, glycerinand water. The pharmaceutical composition is an oil-in-water emulsionand the topical anesthetic and the vasoconstrictor are solubilized inthe water portion of the oil-in-water emulsion. The ratio of theglycerin amount by weight to the sum of the glycerin amount and wateramount by weight in one embodiment is about 20% to about 45%. Further,the sum of the glycerin amount and water amount in one embodiment is atleast 50% w/w of the pharmaceutical composition.

Vasoconstrictors useful in the practice of the invention include, butare not limited to, at least one of phenylephrine hydrochloride,ephedrine sulphate, epinephrine, epinephrine hydrochloride andtetrahydrozoline HCl. Anesthetics useful in the practice of theinvention include, but are not limited to, at least one of benzocaine,benzyl alcohol, dibucaine, dibucaine HCl, pramoxine hydrochloride,tetrocaine, tetracaine HCl, dyclonine, and dyclonine HCl. Thecomposition may further comprise at least one non-ionic emulsifierand/or about 12% w/w to about 18% w/w of a semisolid oleaginousprotectant, and/or at least one antioxidant. In some embodiments a pHadjusting compound with buffering capacity may be added and the pHadjusted to a pH of less than about pH 6.

In one embodiment the invention provides a pharmaceutical compositionfor treating hemorrhoids and/or anorectal disorders in humans comprisingpramoxine hydrochloride, phenylephrine hydrochloride, glycerin andwater. The pharmaceutical composition is an oil-in-water emulsion, andthe pramoxine hydrochloride and phenylephrine hydrochloride aresolubilized in the water portion of the oil-in-water emulsion. The ratioof the glycerin amount by weight to the sum of the glycerin amount andwater amount by weight is about 20% to about 45%. Further, the sum ofthe glycerin amount and water amount is at least 50% w/w of thepharmaceutical composition.

The composition may further comprise at least one non-ionic emulsifier,and/or about 12% w/w to about 18% w/w of a semisolid oleaginousprotectant, and/or at least one antioxidant. A pH adjusting compoundwith buffering capacity may be added and the pH adjusted to a pH of lessthan about pH 6.

In another embodiment the invention provides a pharmaceuticalcomposition for healing hemorrhoids and/or anorectal disorders in humanscomprising about 0.5% w/w to about 3.0% w/w pramoxine hydrochloride,about 0.1% w/w to about 1.0% w/w phenylephrine hydrochloride, glycerin,water, about 0.1% w/w to about 0.3% w/w sodium benzoate, about 12% w/wto about 18% w/w petrolatum, about 0.2% w/w Tenox™, about 0.5% w/w mixedtocopherols, citric acid and at least one non-ionic emulsifier. Thepharmaceutical composition is an oil-in-water emulsion, and thepramoxine HCl and phenylephrine HCl are solubilized in the water portionof the oil-in-water emulsion. The ratio of the glycerin amount by weightto the sum of the glycerin amount and water amount by weight is about20% to about 45%, and the sum of the glycerin amount and water amount isat least 50% w/w of the pharmaceutical composition. The composition mayfurther comprise about 0.1% w/w to about 2.0% w/w carboxymethylcelluloseand about 0.01% w/w to about 1.0% w/w xanthan gum.

The invention further provides a method of preparing a composition fortreating hemorrhoids and/or anorectal disorders in humans comprisingpreparing an oil-in-water emulsion comprising a topical anesthetic, avasoconstrictor, glycerin and water wherein the topical anesthetic andthe vasoconstrictor are solubilized in the water portion of theoil-in-water emulsion. The ratio of the glycerin amount to the sum ofthe glycerin amount and the water amount by weight is about 20% to about45%, and the sum of the glycerin amount and the water amount is at least50% w/w of the pharmaceutical composition.

The invention further provides a method of treatment of hemorrhoidsand/or anorectal disorders in humans comprising administering to theanorectal region a safe and effective amount of the pharmaceuticalcomposition of the invention disclosed herein.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides an anesthetic cream composition which is anoil-in-water emulsion comprising a local anesthetic, a vasoconstrictor,glycerin and water. The inventors have discovered that certain ratios ofglycerin and water facilitate not only the dispersion of water solublelocal anesthetics and/or vasoconstrictors in the composition but alsopromote absorption into human body tissue. The cream of the inventionhas improved prolonged anesthesia particularly as compared to a typicalgel preparation, other creams and ointments.

The cream of the invention may be formulated with petrolatum and anemulsification system, both of which may promote good rub-in propertiesand foster long-term stability under storage conditions. Further, thecomposition may include one or more antioxidants and/or be adjusted toan acidic pH using a composition that has buffering capacity.

The invention also provides a method for treating hemorrhoids and amethod of preparation of the composition of the invention.

As used herein, “hemorrhoids” mean swollen varicose veins in the mucousmembrane inside or just outside the rectum. The composition and methodsof the invention may be used to treat diseases of the anorectum whichmanifest one or more symptoms of itching, discomfort, pain and bleeding.Accordingly, references to use of the composition and/or methods of theinvention for treating hemorrhoids is equally applicable to diseases ofthe anorectum manifesting one or more symptoms in common withhemorrhoids.

The term “pharmaceutical active”, “active pharmaceutical agent”, “activeagent” and “drug” as used herein should be considered to have the samemeaning.

The terms “effective amount” or “therapeutically effective amount” of anactive agent as provided herein is defined as an amount of the agent atleast sufficient to provide the desired therapeutic effect.

The term “glycerin ratio” means the ratio of the weight of glycerin tothe weight of glycerin plus the weight of water in the composition.Preferably this ratio is expressed as a percent.

The term “w/w”, unless otherwise indicated, means weight of a givencomponent or specified combination of components to total weight of thecomposition expressed as a percentage.

A designation that a substance is a solid, semisolid, liquid or gasshould be taken to mean the physical state of the substance in thetemperature range of about 20° C. to about 40° C.

A “vasoconstrictor” means a substance or agent that promotes theconstriction of blood vessels in hemorrhoidal tissue (i.e. shrinks thehemorroidal tissue).

An “anesthetic” means a substance that is capable of producing acomplete or partial loss of feeling.

As used herein, the term “treat” or “treating” or “treatment” means toprovide relief of one or more of the symptoms associated withhemorrhoids. The relief may be provided by ameliorating one or moresymptoms, reducing the hemorrhoid, and/or healing affected tissues, forexample. Accordingly, the treatment of hemorrhoids can include thefollowing: constriction of the blood vessels of the hemorrhoidal tissueand/or providing relief from the discomfort or pain from the burning,itching, swelling, irritation, soreness and/or inflammation ofhemorrhoidal tissue.

The term “petrolatum” refers to petroleum jelly, which is a mixture ofthe softer members of the paraffin or methane series' of hydrocarbons,obtained from petroleum as an intermediate product in the distillation.Petrolatum is typically perceived as soothing when applied to the humanskin.

Anesthetics suitable for use in the practice of the invention andsuitable respective ranges of their amounts include, but are not limitedto, benzocaine (about 5% to about 20% by weight, benzyl alcohol (about1% to about 4% by weight), dibucaine and dibucaine HCl (about 0.25% toabout 1% by weight); lidocaine and lidocaine HCl (about 0.5% to about 5%by weight); pramoxine hydrochloride (about 0.5 to about 1% by weight),tetracaine and tetracaine HCl (about 0.5% to about 1% by weight) anddyclonine and dyclonine HCl (about 0.5% to about 1.0% by weight) ormixtures thereof.

Use of pramoxine HCl as the anesthetic has several advantages. It is along-acting surface anesthetic that fosters the relief of pain withoutthe loss of the touch sensation (e.g. without numbing). Further,pramoxine HCl is water soluble and has a low toxicity profile.

Vasoconstrictors suitable for use in the invention include, but are notlimited to, phenylephrine hydrochloride, ephedrine sulphate,epinephrine, epinephrine hydrochloride and tetrahydrozoline HCl ormixtures thereof. In the embodiments in which phenylephrine HCl is thevasoconstrictor, the phenylephrine hydrochloride is used in an amount upto about 0.35% w/w of the total composition, more preferably about 0.1to about 0.3%, and most preferably about 0.25%.

Glycerin (glycerol) is used in the practice of the invention in anamount of about 10% w/w to about 45% w/w. Further, the sum of theglycerin content and water content should be at least 50% w/w of thecomposition and the ratio of the glycerin content to the sum of theglycerin and the total water content ranges from about 20% to about 45%.Commercially available 96% glycerin 4% water may be used in the practiceof the invention, however any water contained in the commercial glycerinproduct should be included in the determination of total water in thecomposition. Likewise glycerin amounts are based on actual amount of thechemical entity glycerin.

The inventors believe, without wishing to be bound to theory, that theglycerin and water amounts and amount of glycerin to the total amountglycerin and water (e.g. the glycerin ratio) are important factors inimparting some of the desired features of the invention. Glycerin alonecan have a dehydrating effect which would not only potentially have theundesirable property of dehydrating the affected area but also may causean uncomfortable sensation. However, glycerin in combination withsuitable amounts of water has the desired feature of providing hydrationto afflicted areas. As the preferred anesthetics and vasoconstrictorsare water soluble, the water glycerol combination also facilitatespenetration of the active agents into the afflicted area. Both theamounts of glycerin and water, as well as their relative proportions,are believed to be important to optimize the humectant properties ofglycerin, facilitate the penetration of the active ingredients into theafflicted area, and facilitate hydration of the tissues. Hydration isbelieved to facilitate relief of itching, discomfort and pain. Hydrationof the afflicted epithelial tissue is particularly important in theanorectal area since the rectal area is particularly devoid of water incomparison to other body cavities such as the buccal or vaginal cavity.Further improved penetration of the active agents in the afflicted areasis believed to provide improved anesthesia.

In one embodiment pramoxine HCl and phenylephrine HCl are the anesthesiaand vasoconstrictor, respectively, in an oil-in-water emulsion. Glycerinis preferably present at a level, and at a ratio to the total formulaquantity of glycerin and water to optimally promote the hydration ofirritated epithelial tissue with the water phase of the oil-in-wateremulsion. This facilitates delivery of the pramoxine HCl andphenylephrine HCl which are dissolved in the water to afflicted tissue.Preferably the amount of water is sufficient to fully solubilize thepramoxine HCl and phenylephrine HCl. Full solubilization presents thepharmaceutical actives as molecular species in a water medium. If thepharmaceutical actives are suspended in an oleaginous substance (e.g.not solubilized), the pharmaceutical actives are likely to be dispersedas aggregates of molecules.

Pramoxine HCl provides a long-acting surface anesthesia fostering therelief of pain without the loss of the touch sensation (e.g. a numbingfeeling). The combination of pramoxine HCl with the vasoconstrictorphenylephrine HCl is believed to prolong the residence time of thepramoxine HCl at the inflamed/irritated tissue site, thus prolonging theanesthetic effect over a composition containing pramoxine HCl alone.

The composition of the invention may contain one or more antioxidants,preferably antioxidants that scavenge free radical oxygen species.Exemplary antioxidants include about 0.2% w/w Tenox-2™ (i.e. a mixtureof butylated hydroxy anisol (BHA) and propyl gallate dissolved inpropylene glycol) and mixed tocopherols at about 0.5% w/w. As manyactive agents such as pramoxine HCl and phenylephrine HCl, for example,are susceptible to oxidation by free radical species, it is desirable insome embodiments to use at least two antioxidants to provide enhancedprotection against a range of oxidizing agents.

Other antioxidants that may be used include BHT (butylated hydroxytoluene), botanical extract antioxidants, flavinoid antioxidants, sodiumascorbate sodium metabisulphite. The antioxidants promote the chemicalstability of active ingredients such as pramoxine HCl and phenylephrineHCl by protecting against oxidation by free radical oxygen species.

An organic acid may be used to adjust in the pH preferably to an acidicrange below about pH 6 and more preferably a pH range of about 3.5 toabout 4.2. Citric acid at a level of about 0.1% w/w to about 0.3% isexemplary of a suitable acid. The acid not only maintains a pH rangethat is optimal for the active components of the composition of theinvention but also may serve to buffer the composition from alkaliinsult if the composition is put into commercial packaging. Othersuitable organic acids include, but are not limited to, maleic acid,succinic acid and other weak organic acids. Phosphoric acid is alsosuitable for use in adjusting the pH and providing buffer capacity.

It is believed that the use of at least one antioxidant or at least onecompound that adjusts the pH to acidic range and has a bufferingcapacity or both facilitates shelf-life stability by providing anoptimum pH for stability of active ingredients and scavenging of freeradicals which may promote degradation. The buffering capacity providesthe capacity for neutralizing any alkali specie that might be introducedin the manufacturing process or from packaging. In some embodiments atleast two antioxidants are used.

In an embodiment in which pramoxine HCl and phenylephrine HCl are theanesthetic and vasoconstrictor, respectively, it is preferable tomaintain the pH below about pH 6.0 and more preferable to maintain thepH below about pH 4. The low pH is beneficial for reducing, for example,potential degradation of phenylephrine. Maintaining the pH in thepreferred range may be accomplished by including, for example, citricacid in the composition. An acidic environment provides the additionalbenefit of anti-microbial action in addition to facilitating stabilityunder storage conditions.

In one embodiment the oil phase contains about 12% w/w to about 18% w/wof a semisolid oleaginous protectant ingredient such as, for example,petrolatum. Petrolatum is believed to promote good rub-in properties andaccordingly enhance delivery of the active agents. Other materialssuitable for use in the oil phase include, but are not limited to,mineral oil, paraffin, white wax, coca butter, shea butter. The oilphase may comprise a single type of oil or semi-solid oleaginous productor mixtures thereof. Further, a given oil or semisolid oleaginousproduct may contain a mixture of chemically similar chemical species.

Suitable emulsifiers for low pH (e.g. acidic) embodiments of thecomposition are non-ionic emulsifiers which can tolerate a low pH.Suitable emulsifiers include, but are not limited to, esters and ethersof fatty acids and esters and ethers of fatty alcohols and sorbitanesters including ethoxylates and non-ethoxylates and mixtures thereof.Typical compounds used as anionic emulsifiers do not function asemulsifiers at low pH and some cationic emulsifiers may be irritatingwhen left on the epithelial tissues for an extended period of time.

Typically a mixture of ethoxylated and non-ethoxylated emulsifiers areused. In some embodiments, for example in emulsions containing greaterthan 10% of an oleaginous semi-solid such as petrolatum, it is desirableto include an ethoxylated fatty alcohol, that is a solid at roomtemperature and at least one or more additional emulsifiers withviscosity building attributes such as, for example, cetyl alcohol and/orstearyl alcohol. A solid ethoxylated fatty alcohol is believed topromote stability at temperatures around 40° C., (e.g., may, forexample, prevent cheesy appearance upon storage at 40° C.).

In one embodiment of the cream of the invention comprising pramoxineHCl, phenylephrine HCl, glycerin, water, sodium benzoate, about 12% toabout 18% semi-solid petrolatum, a non-ionic emulsifier which is a solidat room temperature, about 0.1% to about 0.3% w/w of citric acid and theantioxidants Tenox-2 (about 0.2% w/w) and mixed tocopherols (about 0.5%w/w), exhibited superior physical/chemical stability in shelf lifetesting. In a cream containing pramoxine/phenylephrine which containedno pH buffers and no antioxidants, the pramoxine degradantn-butoxyphenol was observed upon storage. This degradant was notobserved upon storage of the compound of the composition of theinvention.

The composition of the invention may include one or more preservativessuch as, but not limited to, methylparaben, propylparaben, sodiumbenzoate and phenoxyethanol, hydroxybenzoates, imidazole urea. In someembodiments at least two or more preservatives may be used, one of whichpreferentially dissolves in the water phase of the oil-in-water emulsionand another of which that preferentially dissolves in the oil portion ofthe active water emulsion. For example, the combination of methylparabenwhich is water soluble and propylparaben which is oil soluble may beused in the practice of the invention. Further benzyl alcohol in amountsup to about 1% w/w may be used as an auxiliary preservative.

The composition of the invention may also include chelating agents suchas, for example, disodium edetate.

The composition of the invention may further include emollients andanti-irritants such as, for example including but not limited to, aloevera oil, Vitamin E acetate, D-panthenol, green tea extract, heat-shockproteins and phytosterols.

In one embodiment carboxymethylcellulose and/or xanthan gum may beincluded in the composition of the invention to modify texture, promotea smooth consistency over time and storage conditions, mitigate againstgraininess and/or promote a smooth and shiny appearance. The compositionof the invention is an oil-in-water emulsion not a gel. Accordinglyamounts of carboxymethylcellulose and xanthan gum should be sufficientto impart a smooth appearance to the cream of the invention but atinsufficient levels to form a gel. Carboxymethylcellulose may be used inan amount of about 0.1% w/w to about 2.0% w/w and more preferably about0.25% w/w to about 2.0% w/w. Xanthan gum may be used in an amount ofabout 0.01% to about 1.0%. Aqualon 7MF™ is exemplary of aCarboxymethylcellulose suitable for use in the practice of theinvention. Rodigel 80™ from R. T. Vanderbildt is exemplary of a suitablexanthan gum.

Optionally, menthol may be included in composition of the invention as asensory efficacy cue to provide a user of the composition with animmediate anti-pruritic (e.g. anti-itch) effect and a decided coolingsensation. Typically about 0.01% to about 1.0% w/w menthol may beincluded.

Optionally, fragrances known to those in the pharmaceutical industry maybe included.

The composition of the invention is intended for topical application tothe affected tissue. The composition may be applied intrarectally and/orto the anorectal region. The typical method of use is application one tofour times daily of an aliquot of the composition to the afflictedtissue with gentle rubbing.

The composition of the invention is typically prepared by combining theoil component(s) and the emulsifier(s) and then combining theoil/emulsifier mixture with the water and the glycerin components.Preferably if carboxymethylcellulose and/or xanthan gum are used, theyare dispersed in the glycerin and hydrated with water prior tocombination of the water and glycerin (e.g. water/glycerin component)with the oil/emulsifier component. The oil emulsifier component andglycerin/water component should be combined with vigorous stirring. Insome embodiments it is desirable that the combination process beconducted at elevated temperatures. In an exemplary embodiment thecombining process was conducted at about 70-75° C. The amount of heatingwill vary depending on the oils used and should be sufficient to promoteformation of the emulsion but not so high as to promote degradation ofcomponents.

Components not specifically mentioned may be added at any one of avariety of points in the process as one skilled in the art willappreciate. Typically oil soluble components not susceptible to heatdegradation up to about 100° C. were dissolved in the oil/emulsifiermixture prior to mixing with the glycerin/water dispersion and watersoluble components that have degradation at temperature below about 100°C., were combined in the emulsion mixture after combination of the oilemulsifier and water/glycerin components and cooling of the emulsion tonear ambient temperature typically about 50° C. Further, it ispreferable in some embodiments to add salts and acids after the emulsionis formed as addition prior to forming the emulsion may adversely impactemulsion formation in some cases.

Example 1 Anorectal Cream

The following example describes a pharmaceutical composition, which isexemplary of the oil-in-water emulsion for treating hemorrhoids and/oranorectal disorders of the present invention.

% W/W ACTIVE INGREDIENTS Pramoxine HCl, USP 1.00 Phenylephrine HCl, USP0.250 Glycerin, USP 14.4 White Petrolatum, USP 15.0 INACTIVE INGREDIENTSMethylparaben, NF 0.200 Propylparaben, NF 0.100 Sodium Benzoate, NF0.200 Disodium Edetate USP 0.0500 Mixed Tocopherols Antioxidant 0.500Propyl Gallate and BHA in Propylene Glycol 0.200 Steareth-20 1.00Steareth-2 1.00 Glyceryl Monostearate and Laureth-23 (70/30) 3.00Stearyl Alcohol, NF 5.00 Cetyl Alcohol, NF 5.00 SodiumCarboxymethylcellulose, USP 0.250 Xanthan, NF 0.100 Citric Acid, USP0.200 Aloe Vera Oil 0.100 Vitamin E Acetate, USP 0.100 D-Panthenol, USP1.00 Purified Water, USP 51.35

The composition of Example 1 was prepared by melting the oil component(i.e. white petrolatum for this example) and combining the melted oilwith the emulsifiers, emollients, antioxidants and preservatives (i.e.emulsifiers: steareth-20, steareth-2, glyceryl monosterate andlaureth-23 (70/30) stearyl alcohol and cetyl alcohol; emollients:Vitamin E, aloe vera oil; antioxidants: Tenox 2™ and mixed tocopherols;and preservatives: methyl paraben and propylparaben). The sodiumcarboxymethylcellulose and xanthan gum were dispersed in the glycerinand then hydrated by mixing the glycerin dispersion with water. Thedisodium edetate was added to the glycerin/water dispersion.

The glycerin/water dispersion was combined with oil/emulsifier mixturewith vigorous mixing and with heating to about 70-75° C. Upon thoroughmixing the composition was cooled to about 50° C. and the pharmaceuticalactives, other heat labile components, salts and acids (e.g. sodiumbenzoate, panthenol, and citric acid) were added.

Physical characteristics of the composition of Example 1 were measuredby means known to those skilled in the art. The measured physicalcharacteristics of the composition of Example 1 include SpecificGravity: 0.983; pH: 3.93; and Viscosity: 44,980 cps at the time ofmanufacture, 159,000 cps three days after manufacture and 179,000 cpsseven days after manufacture.

Although the foregoing invention has been described in some detail byway of illustration and examples for purposes of clarity andunderstanding, it will be obvious that certain changes and modificationsmay be practical within the scope of the appended claims. Modificationsof the above-described modes of practicing the invention that areobvious to persons of skill in the art are intended to be included inthe scope of the following claims.

1. A method of treating of hemorrhoids and/or anorectal disorders inhumans comprising administering to the anorectal region a safe andeffective amount of a pharmaceutical composition, the pharmaceuticalcomposition comprising: pramoxine hydrochloride, phenylephrinehydrochloride, glycerin and water wherein the pharmaceutical compositionis an oil-in-water emulsion and the oil-in-water emulsion is a cream,wherein the pramoxine hydrochloride and phenylephrine hydrochloride aresolubilized in the water portion of the oil-in-water emulsion, whereinthe ratio of the glycerin amount by weight to the sum of the glycerinamount and water amount by weight is about 20% to about 45%, and whereinand wherein the composition provides hydration to hemorrhoid and/oranorectal tissue.
 2. The pharmaceutical composition of claim 1, whereinthe sum of the glycerin amount and water amount is at least 50% w/w ofthe pharmaceutical composition.
 3. The pharmaceutical composition ofclaim 1, wherein the vasoconstrictor comprises at least one ofphenylephrine hydrochloride, ephedrine sulphate, epinephrine,epinephrine hydrochloride and tetrahydrozoline HCl.
 4. Thepharmaceutical composition of claim 1, wherein the anesthetic comprisesat least one of benzocaine, benzyl alcohol, dibucaine, dibucaine HCl,pramoxine hydrochloride, tetrocaine, tetracaine HCl, dyclonine, anddyclonine HCl.
 5. The pharmaceutical composition of claim 1, furthercomprising at least one non-ionic emulsifier.
 6. The pharmaceuticalcomposition of claim 1, wherein the at least one non-ionic emulsifierincludes an ethoxylated fatty alcohol that is a solid at roomtemperature.
 7. The pharmaceutical composition of claim 1, furthercomprising a pH adjusting compound wherein the pH adjusting compound hasbuffering capacity and wherein the pH is adjusted to less than about pH6.
 8. The pharmaceutical composition of claim 1, further comprisingabout 12% w/w to about 18% w/w of a semisolid oleaginous protectant.